Synthesis of Estradiol Hydroxamic Derivatives and Their in vitro Antitumor Activities

doi:10.6023/cjoc202412017

Abstract

Cancer continues to be a leading cause of mortality worldwide, claiming millions of lives annually. This underscores the urgent need for the development of highly effective and low-toxicity antitumor agents. In this study, a novel series of steroidal hydroxamic acid derivatives were synthesized through structural modification of estrone. Specifically, an oxime ether-linked hydroxamic acid group was introduced at the 17-position. The in vitro antitumor activity of these compounds was systematically evaluated. The results revealed that the hydroxamic acid-conjugated steroidal derivatives exhibited potent inhibitory effects against a panel of tumor cell lines. Notably, O-(N-hydroxyhexanamido)-3-methoxy-estrophenone-17-oxime (5c) emerged as a standout candidate, demonstrating exceptional antitumor activity. Mechanistic investigations further elucidated that compound 5c induces apoptosis by elevating intracellular reactive oxygen species (ROS) levels, resulting in mitochondrial dysfunction and subsequent cell death. These findings highlight the significant role of the hydroxamic acid moiety in enhancing antitumor efficacy and offer valuable insights for the rational design and development of next-generation antitumor therapeutics.

Key words: hydroxyxamic acid, estrone, anti-tumor activity, apoptosis, reactive oxygen species (ROS)

Cite this article

Ying Li, Zhenghui Liang, Zhiwei Zhong, Youying Wei, Qingran Liu, Junyan Zhan, Chunfang Gan. Synthesis of Estradiol Hydroxamic Derivatives and Their in vitro Antitumor Activities[J]. Chinese Journal of Organic Chemistry, 2025, 45(8): 3017-3027.

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Fig. & Tab. 12

Figure 1. Structures of compounds 1~4

Figure 2. Structural formula of vorinostat (SAHA)

Figure 3. Structures of compounds 5~9

Scheme 1. Synthesis route

Compd.	Skov-3	MCF-7	Hela	T47D	HepG-2	293T
4a	>80	>80	>80	>80	>80	>80
4b	>80	>80	>80	>80	>80	>80
4c	>80	>80	>80	>80	>80	>80
4d	>80	39.48±1.60	70.90±1.85	>80	>80	>80
4e	>80	>80	51.31±1.71	>80	>80	>80
5a	8.05±0.38	9.76±0.12	8.87±0.28	16.12±0.52	30.52±5.46	15.12±2.64
5b	16.89±0.06	14.26±1.60	16.70±0.16	24.21±0.38	14.33±1.22	28.74±0.62
5c	6.47±0.22	5.54±0.08	6.16±0.14	10.06±0.50	7.43±0.87	18.84±0.44
5d	6.98±0.20	9.54±0.13	13.22±0.36	17.58±0.22	21.52±0.26	19.32±1.92
5e	6.64±0.41	8.59±0.57	6.57±0.37	11.58±0.21	9.22±0.34	15.58±0.70
SAHA^b	0.86±0.06	3.6±0.56	3.20±0.51	—	—	73.91±1.88

Table 1. In vitro antiproliferation effects [(IC50±SD]/(μmol•L－1) of compounds 4a~4e and 5a~5e on tumor cells at 72 h

Figure 4. Histogram of the inhibition rate of compound 5c on Hela cells for 72 h

Figure 5. Cell morphology changes of compound 5c on Hela cells for 24 h

Figure 6. (a) Plot of changes and (b) histogram of cell scratching by compound 5c on Hela cells for 24 h

Figure 7. Cell clonogram of the compound 5c on Hela cells for 24 h

Figure 8. (a) Apoptosis graph of Hela cells treated with compound 5c for 24 h and (b) histogram of apoptosis changes

Figure 9. (a, b) ROS plot of compound 5c after 24 h of action on Hela cells, and (c) histogram of ROS changes

Figure 10. (a) Mitochondrial membrane potential of Hela cells treated with compound 5c for 24 h, and (b) histogram of mitochondrial membrane potential change

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